Project Summary: Cannabis is the most commonly used illicit drug, and with increasing availability resulting from expanding legalization, the number of people with cannabis use disorder (CUD) continues to rise. Lack of FDA-approved pharmacotherapies, and limited efficacy of conventional psychotherapies, means that many of those who seek treatment relapse within the first few months. One reason for the modest treatment effects may be because the neural systems at the root of the cognitive and behavioral pathology are not targeted. Neuroimaging studies in drug-dependent individuals have revealed abnormal functional organization in the brain that corresponds to these pathologies, including elevated resting-state functional connectivity (rsFC) in frontal- striatal reward circuitry, including the ventromedial prefrontal cortex and ventral striatum, and reduced rsFC in frontal-parietal cognitive control circuitry, including the dorsolateral prefrontal cortex and parietal cortex. However, while circuit-level alterations appear to be common across substances of abuse, most prior studies have focused on comparing users to non-using controls, rather than comparing users with and without substance use disorders (SUDs). Therefore, it is unclear what neural markers differentiate recreational users from those with SUDs and significant functional impairments. Furthermore, much less is known about resting-state circuit alterations in cannabis users, namely across the addiction spectrum. In this 2-year Diversity Supplement proposal, we seek to evaluate the neural markers differentiating recreational cannabis users from those with CUD by examining the role of reward processing and cognitive control circuitry between these groups. GOAL: The primary objectives of this proposal are to: determine the relationship between frontal-striatal and frontal-parietal rsFC and CUD status (Aim 1), and functional impairment (Aim 2). DESIGN: 60 non- treatment-seeking healthy cannabis users will be recruited (30 with no CUD, 30 with mild, moderate, or severe CUD). This study will involve comprehensive screening and a 3-day inpatient protocol comprising fMRI and behavioral choice tasks and laboratory cannabis self-administration. Structural MRI and rsfMRI data will be collected. Self- and peer-report data on functional impairment will be collected from the participant and a close friend or relative, respectively. We will test the hypotheses that the degree of increased rsFC in the frontal-striatal circuitry and decreased rsFC in the frontal-parietal circuitry will differ between cannabis users with and without CUD (Aim 1), and across levels of functional impairment (Aim 2). Through this 2-year Diversity Supplement proposal, we will acquire critical data needed to provide a foundation for future development of novel neural targets for interventions aimed at reversing or preventing the progression of addiction and functional impairment in cannabis users at different stages of the disease process. Furthermore, this Diversity Supplement will provide Dr. Tonisha Kearney-Ramos with essential training in cannabinoid research and human laboratory methodology which she seeks for the advancement of her career as a clinical addiction neuroscientist. !